Hematologic malignancies, including leukemia, lymphoma, and multiple myeloma, are hazardous diseases characterized by the uncontrolled proliferation of cancer cells. Dysregulated cell cycle resulting from genetic and epigenetic abnormalities constitutes one of the central events. Importantly, cyclin-dependent kinases (CDKs), complexed with their functional partner cyclins, play dominating roles in cell cycle control. Yet, efforts in translating CDK inhibitors into clinical benefits have demonstrated disappointing outcomes. Recently, mounting evidence highlights the emerging significance of WEE1 G2 checkpoint kinase (WEE1) to modulate CDK activity, and correspondingly, a variety of therapeutic inhibitors have been developed to achieve clinical benefits. Thus, WEE1 may become a promising target to modulate the abnormal cell cycle. However, its function in hematologic diseases remains poorly elucidated. In this review, focusing on hematologic malignancies, we describe the biological structure of WEE1, emphasize the latest reported function of WEE1 in the carcinogenesis, progression, as well as prognosis, and finally summarize the therapeutic strategies by targeting WEE1.
Humans ; Protein-Tyrosine Kinases/physiology* ; Hematologic Neoplasms/drug therapy* ; Cell Cycle Proteins/antagonists & inhibitors* ; Nuclear Proteins/antagonists & inhibitors* ; Cyclin-Dependent Kinases ; Molecular Targeted Therapy ; Animals

Osteoarthritis (OA) is the most common degenerative joint disease. Its pathological process is related to inflammatory response, chondrocyte apoptosis, and cartilage degeneration. Hippo-yes-associate protein(YAP) signaling pathway plays an important role in mediating organ size and tissue homeostasis. In recent years, the key effector protein YAP in the Hippo-YAP pathway has become a research hotspot in osteoarthritis. This article introduces the activation process of Hippo-YAP signaling pathway and the biological role of YAP. It reviews the progress of YAP in regulating osteoarthritis by influencing the proliferation and differentiation of mesenchymal stem cells and the proliferation, differentiation, and apoptosis of articular chondrocytes. It analyzed the problems encountered in YAP research in OA, introduces the research potential of YAP in other orthopedic diseases, and provides new ideas for subsequent research in Osteoarthritis.
Osteoarthritis/metabolism* ; Humans ; Signal Transduction ; Protein Serine-Threonine Kinases/physiology* ; Hippo Signaling Pathway ; YAP-Signaling Proteins ; Adaptor Proteins, Signal Transducing/physiology* ; Animals ; Transcription Factors ; Chondrocytes/cytology* ; Cell Cycle Proteins

N⁶-methyladenosine (m⁶A) modification plays a critical role in cell cycle regulation, while the mechanism of m⁶A in regulating mitosis remains underexplored. Here, we found that the total m⁶A modification level in cells increased during mitosis by the liquid chromatography-mass spectrometry/mass spectrometry and m⁶A dot blot assays. Silencing methyltransferase-like 3 (METTL3) or METTL14 results in delayed mitosis, abnormal spindle assembly, and chromosome segregation defects by the immunofluorescence. By analyzing transcriptome-wide m⁶A targets in HeLa cells, we identified polo-like kinase 1 (PLK1) as a key gene modified by m⁶A in regulating mitosis. Specifically, through immunoblotting and RNA pulldown, m⁶A modification inhibits PLK1 translation via YTH N⁶-methyladenosine RNA binding protein 1, thus mediating cell cycle homeostasis. Demethylation of PLK1 mRNA leads to significant mitotic abnormalities. These findings highlight the critical role of m⁶A in regulating mitosis and the potential of m⁶A as a therapeutic target in proliferative diseases such as cancer.
Humans ; Polo-Like Kinase 1 ; Cell Cycle Proteins/metabolism* ; Proto-Oncogene Proteins/metabolism* ; Protein Serine-Threonine Kinases/metabolism* ; Mitosis/physiology* ; HeLa Cells ; Adenosine/genetics* ; Methyltransferases/metabolism* ; RNA, Messenger/metabolism* ; RNA-Binding Proteins/metabolism*

Cell cycle plays a crucial role in cell development. Cell cycle progression is mainly regulated by cyclin dependent kinase (CDK), cyclin and endogenous CDK inhibitor (CKI). Among these, CDK is the main cell cycle regulator, binding to cyclin to form the cyclin-CDK complex, which phosphorylates hundreds of substrates and regulates interphase and mitotic progression. Abnormal activity of various cell cycle proteins can cause uncontrolled proliferation of cancer cells, which leads to cancer development. Therefore, understanding the changes in CDK activity, cyclin-CDK assembly and the role of CDK inhibitors will help to understand the underlying regulatory processes in cell cycle progression, as well as provide a basis for the treatment of cancer and disease and the development of CDK inhibitor-based therapeutic agents. This review focuses on the key events of CDK activation or inactivation, and summarizes the regulatory processes of cyclin-CDK at specific times and locations, as well as the progress of research on relevant CDK inhibitor therapeutics in cancer and disease. The review concludes with a brief description of the current challenges of the cell cycle process, with the aim to provide scientific references and new ideas for further research on cell cycle process.
Cyclin-Dependent Kinases/metabolism* ; Cyclins/metabolism* ; Protein Serine-Threonine Kinases ; Cell Cycle Proteins/metabolism* ; Cell Cycle/physiology* ; Cyclin-Dependent Kinase 2

Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration, increases mitochondrial reactive oxygen species (ROS) production, and accelerates cellular senescence. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These f indings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III, thus providing a new potential target to counteract human stem cell senescence.
Mesenchymal Stem Cells/physiology* ; Cellular Senescence ; Homeostasis ; Cell Cycle Proteins/metabolism* ; Adaptor Proteins, Signal Transducing/metabolism* ; Mitochondria/metabolism* ; Electron Transport Complex III/metabolism* ; Humans ; Cells, Cultured

Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm. There has been a lot of attention to applying these drugs for solid tumor treatment. Recent preclinical study has signified the effectiveness on cell proliferation inhibition in lung adenocarcinoma treated by carfilzomib (CFZ), a second generation proteasome inhibitor. However, no insight has been gained regarding the mechanism. In this study, we have systematically investigated the CFZ functions in cell proliferation and growth, cell cycle arrest, and apoptosis in lung adenocarcinoma cells. Flow cytometry experiments showed that CFZ significantly induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma. MTS and colony formation assays revealed that CFZ substantially inhibited survival of lung adenocarcinoma cells. All results were consistently correlated to the upregulation expression of Gadd45a, which is an important gene in modulating cell cycle arrest and apoptosis in response to physiologic and environmental stresses. Here, upregulation of Gadd45a expression was observed after CFZ treatment. Knocking down Gadd45a expression suppressed G2/M arrest and apoptosis in CFZ-treated cells, and reduced cytotoxicity of this drug. The protein expression analysis has further identified that the AKT/FOXO3a pathway is involved in Gadd45a upregulation after CFZ treatment. These findings unveil a novel mechanism of proteasome inhibitor in anti-solid tumor activity, and shed light on novel preferable therapeutic strategy for lung adenocarcinoma. We believe that Gadd45a expression can be a highly promising candidate predictor in evaluating the efficacy of proteasome inhibitors in solid tumor therapy.
Adenocarcinoma of Lung/pathology* ; Apoptosis/drug effects* ; Cell Cycle Checkpoints/drug effects* ; Cell Cycle Proteins/genetics* ; Cell Line, Tumor ; Forkhead Box Protein O3/physiology* ; Gene Expression Regulation, Neoplastic/drug effects* ; Humans ; Lung Neoplasms/pathology* ; Oligopeptides/pharmacology* ; Proto-Oncogene Proteins c-akt/physiology* ; Up-Regulation

BACKGROUND: The clinical trials emerged centromere protein E inhibitor GSK923295 as a promising anticancer drug, but its function in hepatocellular carcinoma (HCC) remain needs to be fully elucidated, especially as chemotherapy after hepatectomy for liver tumors. We aimed to describe anti-HCC activities of GSK923295 and compare its antiproliferative effects on liver regeneration after partial hepatectomy (PH). METHODS: All subjects were randomized to treatment with either vehicle or GSK923295. Antitumor activity of GSK923295 was assessed by xenograft growth assays. The C57BL/6 mice were subjected to 70% PH and the proliferation was calculated by liver coefficient, further confirmed by immunohistochemistry. The proliferation and cell cycle analysis of liver cell AML12 and HCC cells LM3, HUH7, and HepG2 were investigated using the cell counting kit-8 assay and Flow Cytometry. The chromosome misalignment and segregation in AML12 cells were visualized by immunofluorescence. RESULTS: Treatment with GSK923295 induced antiproliferation in HCC cell lines. It also caused delay on HCC tumor growth instead of regression both in a HCC cell line xenograft model and patient-derived tumor xenograft model. With microarray analysis, CENtromere Protein E was gradually increased in mouse liver after PH. Exposure of liver cells to GSK923295 resulted in delay on a cell cycle in mitosis with a phenotype of misaligned chromosomes and chromosomes clustered. In 70% PH mouse model, GSK923295 treatment also remarkably reduced liver regeneration in later stage, in parallel with the mitotic marker phospho-histone H3 elevation. CONCLUSION The anticancer drug GSK923295 causes a significant delay on HCC tumor growth and liver regeneration after PH in later stage.
Animals ; Antineoplastic Agents ; therapeutic use ; Blotting, Western ; Bridged Bicyclo Compounds, Heterocyclic ; therapeutic use ; Carcinoma, Hepatocellular ; drug therapy ; surgery ; Cell Cycle ; drug effects ; Cell Proliferation ; drug effects ; Chromosomal Proteins, Non-Histone ; antagonists & inhibitors ; Electrophoresis, Polyacrylamide Gel ; Female ; Fluorescent Antibody Technique ; Humans ; Immunohistochemistry ; Liver Neoplasms ; drug therapy ; surgery ; Liver Regeneration ; physiology ; Mice ; Mice, Inbred C57BL ; Real-Time Polymerase Chain Reaction ; Sarcosine ; analogs & derivatives ; therapeutic use ; Xenograft Model Antitumor Assays

BACKGROUNDBrain acid soluble protein 1 (BASP1) is identified as a novel potential tumor suppressor in several cancers. However, its role in thyroid cancer has not been investigated yet. In the present study, the antitumor activities of BASP1 against the growth and migration of thyroid cancer cells were evaluated.

METHODSBASP1 expression in thyroid cancer tissues and normal tissues were examined by immunohistochemical staining and the association between its expression and prognosis was analyzed. pcDNA-BASP1 carrying full length of BASP1 cDNA was constructed to restore the expression of BASP1 in thyroid cancer cell lines (BHT-101 and KMH-2). The cell proliferation in vitro and in vivo was evaluated by WST-1 assay and xenograft tumor models, respectively. Cell cycle distribution after transfection was analyzed using flow cytometry. Cell apoptosis after transfection was examined by annexin V/propidium iodide assay. The migration was examined using transwell assay.

RESULTSBASP1 expression was abundant in normal tissues while it is significantly decreased in cancer tissues (P = 0.000). pcDNA-BASP1 restored the expression of BASP1 and significantly inhibited the growth of BHT-101 and KMH-2 cells as well as xenograft tumors in nude mice (P = 0.000). pcDNA-BASP1 induced G1 arrest and apoptosis in BHT-101 and KMH-2 cells. In addition, pcDNA-BASP1 significantly inhibited the cell migration.

CONCLUSIONSDownregulation of BASP1 expression may play a role in the tumorigenesis of thyroid cancer. Restoration of BASP1 expression exerted extensive antitumor activities against growth and migration of thyroid cancer cells, which suggested that BASP1 gene might act as a potential therapeutic agent for the treatment of thyroid cancer.

Aged ; Animals ; Apoptosis ; genetics ; physiology ; Calmodulin-Binding Proteins ; genetics ; metabolism ; Cell Cycle ; genetics ; physiology ; Cell Line, Tumor ; Cell Movement ; genetics ; physiology ; Cell Proliferation ; genetics ; physiology ; Cytoskeletal Proteins ; genetics ; metabolism ; Female ; Gene Expression Regulation, Neoplastic ; genetics ; physiology ; Humans ; Male ; Membrane Proteins ; genetics ; metabolism ; Mice ; Mice, Nude ; Middle Aged ; Nerve Tissue Proteins ; genetics ; metabolism ; Repressor Proteins ; genetics ; metabolism ; Thyroid Neoplasms ; metabolism ; pathology ; Xenograft Model Antitumor Assays

The ubiquitin-proteasome system (UPS) is a proteasome system widely present in the human body, which is composed of ubiquitin (Ub), ubiquitin activating enzymes (E1), ubiquitin conjugating enzymes (E2), ubiquitin protein ligases (E3), 26S proteasome, and deubiquitinating enzymes (DUBs) and involved in cell cycle regulation, immune response, signal transduction, DNA repair as well as protein degradation. Sperm DNA is vulnerable to interference or damage in the progression of chromosome association and homologous recombination. Recent studies show that UPS participates in DNA repair in spermatogenesis by modulating DNA repair enzymes via ubiquitination, assisting in the identification of DNA damage sites, raising damage repair-related proteins, initiating the DNA repair pathway, maintaining chromosome stability, and ensuring the normal process of spermatogenesis.
Cell Cycle Proteins ; physiology ; DNA Damage ; DNA Repair ; physiology ; Humans ; Male ; Proteasome Endopeptidase Complex ; physiology ; Signal Transduction ; physiology ; Spermatogenesis ; physiology ; Spermatozoa ; Ubiquitin ; physiology ; Ubiquitin-Conjugating Enzymes ; physiology ; Ubiquitin-Protein Ligases ; physiology ; Ubiquitination

BACKGROUNDRetinal degenerative diseases are the leading causes of blindness in developed world. Retinal progenitor cells (RPCs) play a key role in retina restoration. Triamcinolone acetonide (TA) is widely used for the treatment of retinal degenerative diseases. In this study, we investigated the role of TA on RPCs in hypoxia condition.

METHODSRPCs were primary cultured and identified by immunofluorescence staining. Cells were cultured under normoxia, hypoxia 6 h, and hypoxia 6 h with TA treatment conditions. For the TA treatment groups, after being cultured under hypoxia condition for 6 h, RPCs were treated with different concentrations of TA for 48-72 h. Cell viability was measured by cell counting kit-8 (CCK-8) assay. Cell cycle was detected by flow cytometry. Western blotting was employed to examine the expression of cyclin D1, Akt, p-Akt, nuclear factor (NF)-κB p65, and caspase-3.

RESULTSCCK-8 assays indicated that the viability of RPCs treated with 0.01 mg/ml TA in hypoxia group was improved after 48 h, comparing with control group (P < 0.05). After 72 h, the cell viability was enhanced in both 0.01 mg/ml and 0.02 mg/ml TA groups compared with control group (all P < 0.05). Flow cytometry revealed that there were more cells in S-phase in hypoxia 6 h group than in normoxia control group (P < 0.05). RPCs in S and G2/M phases decreased in groups given TA, comparing with other groups (all P < 0.05). There was no significant difference in the total Akt protein expression among different groups, whereas upregulation of p-Akt and NF-κB p65 protein expression and downregulation of caspase-3 and cyclin D1 protein expression were observed in 0.01 mg/ml TA group, comparing with hypoxia 6 h group and control group (all P < 0.05).

CONCLUSIONLow-dose TA has anti-apoptosis effect on RPCs while it has no stimulatory effect on cell proliferation.

Animals ; Apoptosis ; drug effects ; physiology ; Caspase 3 ; metabolism ; Cell Cycle ; drug effects ; physiology ; Cell Hypoxia ; drug effects ; physiology ; Cell Proliferation ; drug effects ; physiology ; Cell Survival ; drug effects ; physiology ; Cells, Cultured ; Cyclin D1 ; metabolism ; NF-kappa B ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Rats ; Rats, Sprague-Dawley ; Retina ; cytology ; Stem Cells ; cytology ; drug effects ; Triamcinolone Acetonide ; pharmacology